Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor

Inhibitors of cyclin-dependent kinases 4 and 6 have been shown to be clinically effective for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced, or metastatic breast cancer. These agents, however, often show neutropenia, likely due to the role of CDK6 in hematopoiesis. Herein described is the discovery of a series of aminopyrimidine-based selective CDK4 inhibitors. Central to our strategy were efficiency-based optimization (LipE and LipMetE), structure-based drug design, and molecular dynamics simulation. The culmination of these efforts resulted in the discovery of PF-07220060 (atirmociclib), which possessed high potency and levels of selectivity for CDK4 over CDK6 that translated to minimal impact on neutrophils while driving efficacy in a mouse ZR75-1 xenograft model.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-12-05
DOI
https://doi.org/10.1021/acs.jmedchem.5c02137
Primary Topic
Advanced Breast Cancer Therapies
Type
article
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article

Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor

Ping Chen, Sajiv K. Nair, Sacha Ninkovic, Louise Bernier et al.
Journal of Medicinal Chemistry
Advanced Breast Cancer Therapies
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Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor

Ping Chen, Sajiv K. Nair, Sacha Ninkovic, Louise Bernier, Julie Cianfrogna, John C. Kath, Lars Anders, Robert S. Kania, Aida Sacaan, Loretta M. Cox, Bernadette Pascual, Na Wei, Lisa D. Marroquin, Judith G. Deal, Britton Boras, Martin P. Edwards, Mehran Jalaie, Neal W. Sach, Matthew Petroski, Gary M. Gallego, Sujin Cho-Schultz, Casey L. Quinlan, Suvi T. M. Orr, Fengjuan Cao, Klaus Dress, Eric F. Johnson, Hong Shen, Cynthia L. Palmer, Jennifer Lafontaine
article en

Abstract

Inhibitors of cyclin-dependent kinases 4 and 6 have been shown to be clinically effective for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced, or metastatic breast cancer. These agents, however, often show neutropenia, likely due to the role of CDK6 in hematopoiesis. Herein described is the discovery of a series of aminopyrimidine-based selective CDK4 inhibitors. Central to our strategy were efficiency-based optimization (LipE and LipMetE), structure-based drug design, and molecular dynamics simulation. The culmination of these efforts resulted in the discovery of PF-07220060 (atirmociclib), which possessed high potency and levels of selectivity for CDK4 over CDK6 that translated to minimal impact on neutrophils while driving efficacy in a mouse ZR75-1 xenograft model.

Journal of Medicinal ChemistryVol. 68(24)
Pfizer (United States) (US), Dynamique du noyau (FR)
Openalex Percentile: Top 43%
Advanced Breast Cancer Therapies
DOISourceOpenAlex
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